As-triazino(5,6-b)-3-amino indoles



United States Patent Oflice 3,510,482 Patented May 5, 1970 3,510,482 as-'I'RIAZINO[5,6-h]-3-AIVIINO INDOLES Jan Mieczyslaw Zygmunt Gladych, Hertford, and John Harold Hunt, Theydon Bois, Essex, England, assignors to Allen and Hanburys Limited, London, England No Drawing. Continuation-impart of application Ser. No. 658,644, Aug. 7, 1967. This application July 16, 1968, Ser. No. 745,089

Claims priority, application Great Britain, Sept. 17, 1963, 36,551/63; Feb. 20, 1964, 7,168/64; Aug. 27, 1964, 35,190/64; July 18, 1967, 33,050/67 Int. Cl. C07d 55/06, 57/34; A6lk 27/00 US. Cl. 260-2475 8 Claims ABSTRACT OF THE DISCLOSURE as-Triazino(5,-6-b)indoles of the formula:

where R is hydrogen, halogen, alkyl of 1-4 carbon atoms, hydroxy, alkoxy of l-4 carbon atoms, nitro, amino or trifiuoromethyl, R is hydrogen, lower alkyl of 1-4 carbon atoms, benzyl or phenethyl; and N is amino, alkylamino (NHR aralkylamino, dialkylamino (NR R hydrazino, or heterocyclic amino wherein R is straight or branched chain alkyl of 1l8 carbon atoms, provided that when N) is amino (NH and R is hydrogen or lower alkyl of l4 carbon atoms, R is not hydrogen, bromo, chloro or nitro; the preferred heterocyclic amino groups are morpholino, piperidino, pyrrolidino, or similar monocyclic saturated nitrogen-containing ring; the preferred aralkyls are benzyl, phenethyl and phenylpropyl, exhibit antiviral activity. N-oxide derivatives with a N O group and pharmaceutically acceptable nontoxic salts are also within the scope of the above designated compounds. Particularly valuable compounds are those substituted in the 3-position with amino moieties, preferably dimethylamino or morpholino.

This application is a continuation-in-part of Ser. No. 658,644, filed Aug. 7, 1967, which is a continuation-inpart of Ser. No. 396,727, filed Sept. 15, 1964, now abandoned.

The present invention is concerned with novel heterocyclic compounds. More particularly, the present invention is concerned with as-triazino(5,6-b)indoles of the general formula:

R2 (I) where R is hydrogen, halogen, alkyl of 1-4 carbon atoms, hydroxy, alkoxy of 1-4 carbon atoms, nitro, amino or trifluoromethyl, R is hydrogen, lower alkyl of 1-4 carbon atoms, benzyl or phenethyl; and N) is amino, alkylamino (NHR aralkylamino, dialkylamino (NR R hydrazino, or heterocyclic amino wherein R is straight or branched chain alkyl of l-l8 carbon atoms, provided that when N is amino (NH and R is hydrogen or lower alkyl of l-4 carbon atoms, R is not hydrogen, bromo, chloro or nitro; the preferred heterocyclic amino groups are morpholino, pyrrolidino, or similar monocyclic saturated nitrogen-containing ring; preferred aralkyls are benzyl, phenethyl and phenylpropyl, exhibit antiviral activity.

N-oxide derivatives with a N O group are a part of the invention as well as pharmaceutically acceptable nontoxic salts of the as-triazino(5,6-b)indoles, of the general formula shown above.

The compounds of Formula I are bases and form acid addition and quaternary ammonium salts. All conventional pharmaceutically acceptable non-toxic salts are included within the scope of the invention.

Among the compounds of the invention, there may be mentioned 3-amino-8-methoxy-as-triazino 5 ,6-b indole,

3-dodecylamino-S-1nethyl-as-triazino 5,6-b indole,

3-benzylamino-S-methyl-as-triazino 5,6-b indole,

3 -hexylamino-5-methyl-as-triazino 5,6-b indole,

3-heptylamino-5-methyl-as-triazino( 5,6-b indole,

3-octylamino-S-methyl-as-triazino 5,6-b) indole,

3-decylamino-5-methyl-as-triazino 5,6-b indole,

3-hexadecylamino-S-methyl-as-triazino (5,6-b indole,

3 -octadecylamino-S-methyl-as-triazino 5,6-b indole,

3 Z-phenethylamino -5-methyl-as-triazino 5,6-b indole,

3 -dimethylamino-as-triazino 5,6-b) indole,

3 -dimethylamino-S-methyl-as-triazino 5,6-b indole,

3 -methylamino-S-methyl-as-triazino 5,6-b indole,

3 -ethylamino-S-methyl-as-triazino 5,6-b indole,

3 -propylamino-5-methyl-as-triazino 5,6-b indole,

3 isopropylamino-5-methyl-as-triazino 5,6-b) indole,

3 -butylamino-5-methyl-as-triazino 5.6-b indole,

3 -amylamino-5-methyl-as-triazino 5,6-b indole,

3 -isoamylamino-5-methyl-as-triazino 5,6-b indole,

3-piperidino-5-methyl-as-triazino 5,6-b indole,

3-dimethylamino-5-methyl-8-chloro-as-triazino 5,6-b)

indole,

3-morpholino-5-methyl-as-triazino 5,6-b indole,

lauriodide of 3-ethylamino-5-methyl-as-triazino 5,6-b)

indole,

methiodide of 3-decylarnino-5-methyl-as-triazino 5,6-b)

indole,

bis-1,10-decamethylene diiodide of 3-methylamino-5- methyl-as-triazino 5,6-b indole,

3-ethylamino-5 -methyl-as-triazino 5 ,6-b indole hydrochloride,

3- (Z-phenethylamino) -5-methyl-as-triazino (5 ,6-b indole hydrochloride, I

3-benzylamino-S-methyl-as-triazino 5 ,6-b indole hydrochloride,

3-piperidino-5-methyl-as-triazino 5,6-b indole hydrochloride,

3-morpholino-5-methyl-as-triazino(5,6-b)indole hydrochloride,

3-dimethylamino-S-methyl-as-triazno 5,6-b indole hydrochloride,

and 5 -ethyl-3 -m ethylamino-as-triazino( 5,-6-b indole.

The compounds of Formula I may be prepared by the cyclization of isatin ,B-thiosemicarbazones of the general formula NN H C SN H2 R1 QT n R (III) wherein R and R have the meanings given above and then converting the compounds of Formula III to compounds of Formula I by conventional methods.

The thiosemicarbazones of Formula II may be cyclized give the compounds of Formula III by, for example, refluxing in the presence of ammonia or aqueous potassium carbonate. Alternatively, the thiosemicarbazones need not be isolated in which case thiosemicarbazide and the isatin of formula I't (IV) wherein R and R have the meanings given above, are refluxed together in aqueous potassium carbonate solunon.

Compounds of Formula I may be then prepared by reacting a 3-mercapto-as-triazino(5,6-b)indole of Fornula III with an aminating agent, which may be for instance, ammonia, hydrazine, a primary amine such as m alkylamine; a secondary amine such as dimethylamine; or a heterocyclic amine such as morpholine or piperidine. A S-methylmercapto compound may similarly be employed. The compound of Formula III may be heated, under reflux, with the aminating agent in an inert solvent such as butanol or an excess of the reacting amine may be .ised as the solvent. Alternatively, if the aminating agent is a low boiling amine, an alcoholic solution of it may be heated in a sealed tube with the compounds of Formula [II. The latter, in the solid form, are mainly in the 3 thione structure (C=S).

The reaction of a compound of formula III with hydrazine yields a 3-hydrazino-as-triazino(5,6-b)indole. The mercapto compound may, for example, be heated with hydrazine hydrate.

Compounds in which R is benzyl or phenethyl are prepared by using as starting material an isatin so substituted or by alkylating a compound in which R is hydrogen with a halide such as benzyl chloride or phenethyl chloride.

If desired, the basic compounds of Formula I obtained by any of the processes given above may be quaternized or converted into their salts with inorganic or organic acids.

The isatin starting materials are either known, prepared by known methods, or disclosed in copending application Ser. No. 745,124, filed on the same day as this application and identified as Case No. J13 on the first page thereof.

For the purpose of further illustration of this invention, the following examples are set forth in detail below.

EXAMPLE 1 Preparation of 3-mercapto-5-methyl-as-triazino 5, 6-b indole (a) 6.0 g. of N-methylisatin thiosemicarbazone was suspended in 1.5 l. of water containing 15 ml. of ammonia solution of sp. gr. 0.880 and the mixture was boiled under reflux for 24 hours. After cooling, a small amount of insoluble material was removed by filtration and discarded. The filtrate was evaporated under reduced pressure to about one third of its volume and, after cooling, the yellow solid which separated was filtered otf and recrystallized from 50% aqueous dimethylformamide, 3- mercapto methyl as triazino (5,6-b)indole was obtained, M.P. 279-281 C.

The following compounds were prepared in a similar manner:

3-mercapto-as-triazino(5,6-b)indole, M.P. higher than 360 C. 3-mercapto-S-ethyl-as-triazino(5,6-b)indole, M.P. 294 C. 3-mercapto-5-propyl-as-triazino 5,6-b indole, M.P.

(b) 5 g. of N-methylisatin thiosemicarbazone was suspended in ml. of Water containing 4.4 g. of potassium carbonate and the mixture was boiled under reflux for 75 minutes. The orange colored solution was cooled, diluted with 100 ml. of water and acidified with acetic acid, the yellow solid which separated was filtered off and rewith water, dried at 100 C. and recrystallized from a large volume of methanol to give 3-mercapto-5-methylas-triazino(5, 6-b)indole, M.P. 278282 C.

The following compounds were prepared in a similar manner:

(c) 16 g. of N-methylisatin, 10 g. of thiosemicarbazide and 21 g. of potassium carbonate were boiled under reflux in 500 ml. of water for 7 hours. A small amount of insoluble material was removed by filtration and discarded and the filtrate was cooled and acidified with acetic acid. The solid which separated was filtered off, washed with water and dried at 100 C. to give 3-mercapto-5-methylas-triazino-(S(6-b)indole, M.P. 275 -281 C.

The following compounds were prepared in a similar manner:

3-mercapto-7-methoxy-as-triazino (5,6-b indole, M.P.

3-mercapto-5-propyl-8-chloro-as-triazino(5,6-b)indole,

M.P. 270275 C.

EXAMPLE 2 Preparation of 3-hydrazino-5-methyl-as-triazino(5,6-b) indole 2.75 g. of 3-mercapto-5-methyl-as-triazino(5,6-b)indole was boiled under reflux for 30 minutes with 20 ml. of hydrazine hydrate. The mercapto compound rapidly dissolved giving a red solution which soon commenced to deposit yellow needles. The mixture was cooled, the product filtered off and recrystallized from ethanol to give 3-hydrazino-5-methyl-as-triazino(5,6-b)indole, M.P. 221223 C.

EXAMPLE 3 Preparation of 3-dodecylamino-5-methyl-as-triazino (5 ,6-b indole 1 g. of 3-mercapto-S-methyl-as-triazino(5,6-b)indole and 4 g. of dodecylamine were heated together at C. for 8 hours. On cooling, a solid separated. Ether was added, the solid filtered off and recrystallized from ethyl acetate, M.P. 119120 C.

EXAMPLE 4 Preparation of 3-benzylamino-5-methyl-as-triazino (5 ,6-b indole 4.3 g. of 3-mercapto-S-methyl-as-triazino(5,6-b)indole and 11 ml. of benzylamine were heated together at 130 C. for 8 hours. The product obtained on cooling and after addition of methanol, was filtered 01f, recrystallized from ethanol. Colorless hexagonal plates, M.P. 224 C.

The following compounds were prepared in a similar manner:

S-hexylamino 5 methyl-as-triazino(5,6-b)indole, M.P.

3-heptylamino 5 methyLas-triazino(5,6-b)indole, M.P.

3-octylamino methyl-as-triazino(5,6-b)indole, M.P.

3-decylamino 5 methyl-as-triazino(5,6-b)indole, M.P.

S-hexadecylamino 5 methyl-as-triazino(5,6-b)indole,

M.P. 112 C.

3 octadecylamino 5 methyl as triazino(5,6 b)

indole, M.P. 99 C.

3-(2-phenethylamino)-5-methyl-as-triazino(5,6 b)indole,

M.P. 186 C.

EXAMPLE 5 Preparation of 3-dimethylamino-as-triazino( 5 ,6-b indole 1 g. of 3-mercapto-as-triazino(5,6-b)indole and 20 ml. of a 33% solution of dimethylamine in ethanol were heated in a sealed tube at about 150 C. for 8 hours. After cooling, the tube was opened and the yellow crystals which had separated were filtered off and recrystallized by extraction with ethanol in a Soxhlet extractor. The product was obtained as pale yellow plates, M.P. 342 to 346 C.

Alkylation of the product in the conventional manner with benzyl or phenethyl chloride or bromide in the presence of base gives the S-benzyl or S-phenethyl product, respectively.

The following compounds were prepared in a similar manner to the preparation of 3-dimethylamino-as-triazino- (5,6-b)indole:

3-dimethylamino-5-methyl-as-triazino (5,6-b indole, M.P. 3qhl hy inino-5-methyl-as-triazino(5,6 b)indole, M.P. 3-e ti1g la iino 5 methyl-as-triazino(5,6-b)indole, M.P. 3-ZrEpyl2inino-5-methyl-as-triazino(5,6 b)indole, M.P. 3-i:320 ilamino-S-methyl-as-triazino(5,6-b)indole, M.P. 3-b 3t yla n iino 5 methyl-as-triazino(5,6-b)indole, M.P. 3-ziifii lagino 5 methyl-as-triazino(5,6-b)indole, M.P. 3di my amino-S-methyl-as-triazino(5,6 b)indole, M.P. 31 iizeri ho 5 methyl-as-triazino(5,6-b)indole, M.P.

EXAMPLE 6 Preparation of 3-dimethylamino-5-methyl-8-chloro-astriazino(5,6-b)indole 1 g. of 3-mercapto-5-methyl-8-chloro-as-triazino(5,6- b)indole and 20 ml. of a 33% solution of dimethylamine in ethanol were heated in a sealed tube at about 150 C. for 18 hours. The tube was allowed to cool and was opened. The yellow crystals which had separated were filtered off and recrystallized from methanol. The product was obtained as glistening pale yellow needles, M.P. 217-218 C.

EXAMPLE 7 Preparation of 3-morpholino-5-methyl-as-triazino- (5,6-b)indole A mixture of 1 g. of 3-rnercapto-S-methyl-as-triazino- (5,6-b)indole and 5 ml. of morpholine was boiled under reflux for 8 hours, during which time the solid dissolved to a deep red solution and hydrogen sulphide was evolved. On cooling, a yellow solid separated. A little methanol was added and the solid was removed by filtration. Recrystallized from 25% aqueous alcohol, it had M.P. 169170 C.

EXAMPLE 8 Preparation of the lauriodide of 3-ethylamino-5-methylas-triazino 5, 6-b indole A solution of 1.7 g. of 3-ethy1amino-5-methyl-as-triazino(5,6-b)indole and 4.44 g. of lauryl iodide in 25 ml.

of ethyl methyl ketone was boiled under reflux for 30 hours. After cooling and addition of ether, the precipitate, a gum, was triturated with acetone and twice recrystallized from ether containing 10% ethanol. The quaternary iodide was obtained, M.P. C.

EXAMPLE 9 Preparation of the methiodide of 3-decylamino-5-methylas-triazino 5 ,6-b indole A solution of 2 g. of 3-decylamino-S-methyl-as-triazino(5,6-b)indole in 25 m1. of ethyl methyl ketone was boiled under reflux with 1 ml. of methyl iodide for 6 hours. The solid was filtered off, washed with acetone and recrystallized from ethanol. 1.5 g. of methiodide was obtained as golden yellow crystals, M.P. 253 C.

EXAMPLE 10 Preparation of the bis-1,10-decamethylene diiodide of 3- methylamino-S -methyl-as-triazino 5 ,6-b indole A mixture of 1 g. of 3-methylamino-5-methyl-as-triazino(5,6-b)indole and 1 g. of decamethylene diiodide in 25 ml. of ethyl methyl ketone was boiled under reflux for 30 hours. After cooling, the orange solid was filtered 01f, and recrystallized from a mixture of two parts of ethanol and three parts of ether. The bis-quaternary salt was obtained as orange crystals, M.P. 217 C.

EXAMPLE 11 Preparation of 3-ethylamino-5-methyl-as-triazin0- (5 ,6-b indole hydrochloride 1 g. of 3-ethylamino-S-methyl-as-triazino(5,6-b)indole was dissolved in 20 ml. of 8% hydrogen chloride in methanol. On addition of 200 ml. of ether, the salt separated as yellow microcrystals, which after drying in vacuo, melted at 262 C.

The following compounds were prepared in a similar manner:

3-(2-phenethylamino)-5-methyl-as-triazino(5,6 b)indole hydrochloride, M.P. 220 C.

3-benzylamino-5-methyl-as-triazino 5 ,6-b indole chloride, M.P. 213 C.

3-piperidino 5 methyl-as-triazino(5,6-b)indole hydrochloride, M.P. 222 C.

3-morpholino 5 methyl-as-triazino(5,6-b)indole hydrochloride, M.P. 234 C.

3-dimethylamino-5 -methyl-as-triazino( 5,6 b)indole hydrochloride, M.P. 256 C.

EXAMPLE 12 Preparation of 3-amino-S-methoxy-as-triazino- (5,6-b)indole 13 g. of S-methoxyisatin and 11 g. of aminoguanidine bicarbonate were dissolved in 150 ml. of glacial acetic acid and refluxed for one hour. The orange solid which separated on cooling, recrystallized from glacial acetic acid, gave the acetate of S-methoxyisatin guanylhydrazone. A solution of 10 g. of S-methoxyisatin guanylhydrazone acetate in 2 l. of Water was treated with 20 ml. of ammonia [sp. gr. 0.880] and refluxed 2 hours The free guanylhydrazone which separated was redissolved by boiling and after a time a greenish yellow solid separated. On cooling, the solid was filtered off and recrystallized from aqueous dimethylformamide to give 4 g. of 3-amino- 8-methoxy-as-triazino(5,6-b)indole, M.P. 335 C.

EXAMPLE 13 The following listed products are prepared by treating the corresponding listed starting materials with the appropriate amine according to the procedures described in Examples 5 and 7.

Product.--5-methyl-3-morpholino 8 trifluoromethylas-triazino(5,6-b)indole.

Starting materials.--3mercapto 5 methyl 8 trifluoromethyl-as-triazino(5,6-b) indole and morpholine.

hydro- 7 Prduct.3-dimethylamino 8 fluoro methylas-triazino 5 6-'b indole.

Starting marerials.-3-mercapto-8 fluoro 5 methylas-triazino(5,6-b)indole and dimethylamine.

Product.-8 butyl '5 methyl 3 morpholino-as-tri- The compounds of the invention possess antiviral activity. They are particularly active against rhinoviruses and have been evaluated in the tube dilution test described below.

Tube cultures of diploid human embryonic lung azino(5,6-b)indole. 5 (WI-26) cells were obtained from Baltimore Biological Starting materials.S-butyl-S-methyl 3 mercapto-as Laboratories in Eagles Minimum Essential Medium triazino(5,6-b)indole and morpholino. with 'fetal calf serum.

Product.-3-dimethylamino 5,8 dimethyl as tri- The medium was aspirated off the cultures and replaced azino(5,6-b)indole. 10 with 1 ml. of growth medium [Eagles Minimum Es- Starzing materials.3-mercapto5,8 dimethyl as-trisential Medium with nonessential amino acids, prepared azino(5,6-b)indole and dimethylamine. as described by Eagle, Science 130, 432 (1959)] and Pr0duct.-8-methoxyS-methyl 3 morpholino as- 10% fetal calf serum. The medium of paired cultures was triazino(5,6-b)indole. supplemented with 500, 100, 20 and 4 1 ml. of the com- Starting materials.8-methoxy-5-methyl-3 mercaptopound under test. Four cultures were used as untreated as-triazino(5,6-b)indole and morpholine. controls. The cultures were incubated at 34 C. in a Pr0duct.8-butoxy-5-methyl 3 dimethylamino asroller drum (l2 r.p.h.). After 3 days the cultures were triazino(5,6-b)indole. examined microscopically for evidence of toxicity of Starting materials.-8-butoxy-5-methyl 3 mercaptothe compound, that is, alteration in cell morphology obas-triazino(5,6-b)indole and dimethylamine.v served in unstained cultures at 100x magnification. The

Pr0duct.-8-bromo-5 methyl 3 morpholino asmaximum compound concentration providing no indicatriazino(5,6-b)indole. tion of toxicity in either of the two cultures was the Starting materiaIs.8-bromo-5-methyl 3 mercaptomaximum well-tolerated concentration. as-triazino(5,6-b)indole and morpholine. The tube cultures described above were then used for the activity determination. Five-tenths ml. of an appro- EXAMPLE 14 priate dilution of virus in growth medium containing 10 8-hydroxy-5-methyl-3-morpholino as triazino(5,6-b) TCID (tissue culture infective dose, that is, dose caushldole is Prepared y treating the 8'methoxy Compound ing infection of 50% of the culture) were added to 40 of Example 13 with refluxing 48% HBI for 1-2 hours cultures. Five-tenths ml. of growth medium were added in an atmosphere of nitrogen to four cultures to be used as cell controls. The cultures were then incubated at 34 C. Excess virus or growth EXAMPLE 15 medium was removed after 1 hour and 1 ml. of growth y morpholino as medium was added to each culture. Four non-infected ill-dole is P p y treating the s-hromo compound of cultures used as cell controls and eight infected cultures Example 13 With liquid ammonia in the Presence of a 35 used as virus controls were maintained in unsupplemented Small amount of pp and Powdered CUPTOUS chloride medium. Eight infected cultures were used to determine in a closed Pressure Vessel at for hoursthe antiviral activity of each compound concentration;

these received, 1, 1/5, 1/25, and 1/ 125 WTD (well toler- EXAMPLE 16 ated dose) of test compound diluted with the growth 5 g. of 3-mercapto-S-methyl-as-triazino(5,6-b)indole medium. The cultures were rolled at 34 C. The cultures was dissolved in 65 ml. of 10% sodium hydroxide and were examined microscopically after four days and scored cooled in ice. To the red solution was added, dropwise on the basis of extent of cytopathic effect. 1059, 2060, with stirring, 30 ml. of 30% hydrogen peroxide. When and HGP in the table below designate particular strains the vigorous reaction had subsided, the yellow mixture of rhinovirus. The results are stated as a therapeutic ratio, was stirred for minutes, then diluted with water and 45 the maximum concentration of compound tolerated by acidified with acetic acid. The yellow solid was filtered the cultures over the minimum concentration which inoff and recrystallized from pyridine, M.P. 345 C. hibits cell destruction by the virus.

Comp.

No. R R N) 1059 HGP 2060 1689 H CH3 NCHizHzs EGO/ 4 1075 H CH N(CH3)2 500/100 500/100-20 500/20-100 168i H CH3 N 0 100/100 500/500-100 500-100/100 A mixture of 1.0 g. (0.005 mole) of this 3-hydroxy Compound 1675 is also active against vaccinia virus compound, 4.0 ml. of POCl and 2.0 ml. of dimethylboth in the common plaque inhibition test, and in the aniline was refluxed for 0.75 hour, cooled slightly, and mouse tail infection at an oral dose of 400 mg./kg. :arefully poured into 75-100 g. of cracked ice. The brown The compounds of the invention may be formulated solid was filtered off, washed with water, dried, and refor use in a manner well known to pharmaceutical chemcrystallized from an ample quantity of ethanol to give M5 y Combining them With Standard Pharmaceutical 3-chloro-5-methyl-as-triazino(5,6-b)indole, M.P. 219.5- Cipients to form tablets, capsules, ointments and intranasal 22050 preparations. The oral formulations may contain between To 22 ml. of cone. H 80 cooled to 0 C. is added 9 a 1 and In31y be administered times 1.7 g. (0.0077 mole) of the above 3-chloro compound, yfollowed by dropwise addition of 0.45 ml. of cone. HNO T preparation of these pharmaceutical compositions The contents are stirred at 0 C. for 3 /2 hours and poured is llhlstlamd belowsnto 100 g. of crushed ice. The precipitated solid is co'l EXAMPLE 17 lected and recrystallized from dirnethylformamide to C 1 give 3-chloro-5-methyl-S-nitro-as-triazino(5,6 b)indole, apsu es 300 kg. of one of the compounds of this invention,

Reaction of this compound with morpholine by rfifor instance, 3-dimethylamino-S-methyl-as-triazino(5,6- [hlXihg in Toluene for an hour gives y p )-indole, is finely divided in a comminuting mill to prolino-8-nitro-as-triazino(5,6-b)indole. duce a 60 BS. mesh powder. This powder is filled into No. 1 hard gelatin capsules so that each capsule contains 300 mg. of the active ingredient.

EXAMPLE 18 Tablets 3.00 kg. of one of the compounds of this invention, for example, 3 morpholino S-methyl-as-triazino(5,6-b) indole, 300 g. of maize starch, 400 g. of lactose and 80 g. of hydrolyzed gelatin are mixed together, then sufficient distilled Water is added to produce a damp cohesive mass. screen to produce 20 BS. mesh granules. The dried granduce granules which are dried and then passed through a screen to produce 20 BS. mesh granules. The dried granules are mixed with 300 g. of maize starch, 800 g. of microcrystalline cellulose, 60 g. of polyethylene glycol 4000 and 60 g. of magnesium stearate. The lubricated granules are compressed on a suitable tabletting machine to produce tablets each weighing 5'00 mg. and containing 300 mg. of 3-morpholino-5 -methyl-as-triazino(5,6b)indole.

EXAMPLE 19 N R1 J N wherein R is hydrogen, halogen, alkyl of 1-4 carbon atoms,

hydroxy, alkoxy of 1-4 carbon atoms, amino or trifluoromethyl;

R is hydrogen or lower alkyl of 1-4 carbon atoms,

R is straight or branched chain alkyl of 1-18 carbon atoms; and

N) is amino, benzylamino, phenethylamino, NHR

NR R hydrazino morpholino, or piperidino,

with the proviso that when N) is amino, R is not hydrogen, or halogen,

or a pharmaceutical acceptable acid addition salt thereof. 2. A compound as claimed in claim 1, in which N) is N(CH NHCH or morpholino.

3. A compound as claimed in claim 1, in which R is at the 8-position.

4. A compound as claimed in claim 2, which is 3-dimethylamino-5-methyl-as-triazino(5,6-b)-indo1e.

5. A compound as claimed in claim 2, which is 3- morpholino-S-methyl-as-triazino (5,6-b indole.

6. A compound as claimed in claim 1, which is 3- methylamino-S-methyl-as-triazino (5 ,6-b indole.

7. A compound as claimed in claim 1, which is 8- methoxy S-methyl 3 morpholino-as-triazino(5,6-b)indole.

8. A compound as claimed in claim 1, which is 8- hydroxy-5-methyl-3-morpholino-as-triazino(5,6-b)indole.

References Cited Chemical Abstracts, Sixth Collective Index, vols. 51-55, 195761, Subjects SP-Z, p. 11,934.

Allen & Hanburys Ltd., Chemical Abstracts, vol. 63, p. 13,295 (1965).

ALEX MAZEL, Primary Examiner J. TOVAR, Assistant Examiner U.S. Cl. X.R. 

